The present invention is directed to chemo-therapy of cancer.
A major reason for failure of treatment of cancer patients is resistance to conventional chemo-therapeutic agents. One type of drug resistance, called multi-drug resistance (MDR) is characterized by cross-resistance to functionally and structurally unrelated chemotherapy drugs, such as doxorubicin, vincristine (VCR), vinblastine (VLB), colchicine, and actinomycin D. A number of drugs appear to be active in modifying MDR in model systems, including the calcium channel blocker, verapamil (VRP), the calmodulin inhibitor, trifluoperazine, the anti-arrhythmic drug, quinidine, reserpine, cyclosporin A, Vinca alkaloid analogs, dihydropyridines, and pyridine analogs. Thus, it can be seen that agents that reverse MDR apparently do not seem to have common features. Although several of these MDR-reversing agents have been or are now being tested clinically in cancer patients, they have largely failed to enhance sensitivity to the chemotherapeutic agent. Instead, serious toxicities develop at or below plasma drug levels required for MDR reversal in vitro.
A tricyclic compound, phenoxazine, has been found to potentiate the uptake of VCR and VLB in MDR GC.sub.3 /Cl and KBCh.RTM.-8-5 cells to a greater extent than verapamil. While this discovery has utility and holds promise, it would be desirable to identify derivatives of phenoxazine which would modulate MDR and which show even higher stability and lower toxicity.